Age Dependent Effects of Early Life Stress in the Brain: Implications for
Psychopathology and Treatment Outcome.
Susan van den Boogaard Date: 06-10-2020
Student ID: 10500197 Word count: 10209 Supervisor: Karina Borja Co-assessor: Harm Krugers
MSc in Brain and Cognitive Neuroscience, University of Amsterdam Behavioural Neuroscience Track
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Abstract
Early life stress is referred to as a stressful or traumatic event during childhood. Early life stress is thought to alter activity in specific brain areas in order to better cope with the stress inducing situation. However, once the stressors are absent these alterations seem to persist and may lead to pathology. The current literature review found that the impact that early life stress has on the brain is age-dependent and may reflect different developmental pathways between victims and non-abused individuals, as in adult cohorts, the stressful situation usually happened several years before the scanning age. Thus, in order to avoid potential confounds in the existing literature about the impact that early life stress has in the brain, in this thesis, I argue that findings should be considered carefully emphasizing the age, as well as the time between when the traumatic event occurred and the time of the assessment, providing examples of studies that seem contradictory in the reported findings. In order to show these apparent inconsistencies, I review studies involving functional magnetic imaging within four cognitive domains, well known to be affected by early life stress that include: threat, reward, emotion and executive functions are reviewed with the associated changes in brain activity. As result, we can observe that depending on the age of the cohort, specific brain areas seem to be affected by early life stress. In contrast, findings seem to be more consistent when participants ages are closer, than when children and adults are compared for example. Moreover, findings in the brain activity that take into consideration the life stage of the victims of early life stress can help optimize the therapeutic treatment to address potential psychopathology. Together, the current review shows that emphasizing the participants’ age, type of trauma, age of onset and individual differences are necessary to characterize the neural and behavioural effects of early life stress, and to optimize the treatments for the victims.
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Introduction
Early Life Stress (ELS) refers to a stressful event during childhood, including negative events such as neglect, emotional, physical and sexual abuse (Cisler, Privratsky, Smitherman, Herringa, & Kilts, 2018; Heim & Binder, 2012; Lupien, McEwen, Gunnar, & Heim, 2009; Metz et al., 2018; Pechtel & Pizzagalli, 2011). These events cause prolonged stress and thereby exceed the child’s coping strategies and resources (Heim & Binder, 2012). Regrettably, current day childhood adversity is still quite common in our society. In 2009 the National Child Abuse and Neglect Data System (NCANDS) revealed that within the USA 1,500,000 children were victims of maltreatment, however, the actual numbers are probably even higher, since most cases of child maltreatment remain unreported (NCANDSD, 2009). Furthermore, it seems that in western countries the prevalence of early life stress is about 30%-40% amongst the population (Aust et al., 2014).
In the last years, an extensive amount of research has investigated the influence of ELS on further development in life. Multiple studies report effects of ELS on different domains including cognition, emotions, language, intelligence and academic success, considerable effort has been put into compiling them in multiple reviews to give a global overview on how ELS might influence these processes (Demir-lira et al., 2016; McCrory, Brito, & Viding, 2011; McCrory, Ogle, Gerin, & Viding, 2019). If we look at the research done on these domains independently, Metz and colleagues (2018) found that ELS has an influence on working memory and integration of emotion. Compared to individuals who did not suffer abuse during childhood, people that have experienced ELS show a decrease in working memory performance task while they experience less interference for negative words. In addition, detriments in emotional processing have been reported that include emotion regulation, emotional perception, working memory, and decision making (Pollak, Cicchetti, Hornung, & Reed, 2000; Pollak, Klorman, Thatcher, & Cicchetti, 2001). Furthermore, detriments have also been observed in academic success, executive functions, language abilities and intellectual performance (Bauer, Hanson, Pierson, Davidson, & Pollak, 2009; Bos et al., 2009; Cohen, Lojkasek, Zadeh, Pugliese, & Kiefer, 2008; Colvert et al., 2008; Mueller et al., 2010; Pollak et al., 2010).
Some of the cognitive deficits have been coupled to alterations in the brain structure of individuals that suffered from ELS. For example, decreases in the volume of the hippocampus, amygdala, insular cortex (IC), anterior cingulate cortex (ACC), orbitofrontal cortex (oFC), prefrontal cortex (PFC) and the corpus callosum (CC) have been reported (Andersen et al., 2008; Aust et al., 2014; Baker, Williams, Heaps, & Paul, 2013; Cohen et al., 2005; Hanson et al., 2010; Hanson, Nacewicz, et al., 2015; Thompson & Gullone, 2003). However, these results are not consistent and vary, for example, Aust and colleagues (2014) found that ELS exposure was negatively correlated to the volume of the hippocampus, only if the individuals were unable to classify another person’s shown emotion. These structural changes may be related to the diversification in working memory reported by Metz and colleagues (2018), since the hippocampus plays a central role in various aspects of memory (Fanselow & Poulos, 2005). Contrary, Cohen et al. (2006) using a comparable same aged participant sample as Fanselow and Poulos (2005) failed to show any difference in hippocampal and amygdala volume, but instead they found a decrease in IC and ACC volume. This is in line with the
5 results of Baker et al. (2013) who in a same aged study population also showed a reduction in ACC and IC volume. This decrease in ACC and ICC volumes may be related to the functional disruptions shown in the study of Pollak et al. (2000), Metz et al. (2018) and Pollak et al. (2019), since the IC and the ACC are main components for emotional regulation and decision making, skills diminished in ELS victims (Gu, Liu, Van Dam, Hof, & Fan, 2013; Shenhav, Botvinick, & Cohen, 2013) Intriguingly, they only found a volume decrease of the ACC and ICC in individuals scanned during adolescent and not in individuals that were scanned during childhood (Baker, Williams, Heaps, et al., 2013).
Additional to the alterations in brain structure, research has shown differences in the brain activity of individuals who underwent ELS, specifically, in the functional connectivity of brain networks at rest. Hyperconnectivity was found between the amygdala and the dorsolateral prefrontal cortex (dlPFC) within adults suffered from ELS (Fan et al., 2014; Fonzo et al., 2019; Kaiser et al., 2017). Also, hyperactivity between the left ventral ACC and the left amygdala, the superior frontal gyrus and right ACC, dorsal ACC and the right ACC, and between the ventromedial PFC in adolescent suffered from ELS was found (Cisler et al., 2018; Kaiser et al., 2017). Additionally, the left amygdala and the right ACC showed hyperactivity within children suffered from ELS compared to individuals that did not experience ELS (Thomason & Marusak, 2017; Zielinski et al., 2018). Furthermore, seed-based connectivity has shown decreased activation of the left pallidus, nucleus accumbens, the left basal ganglia (Dillon, Holmes, Birk, Brooks, Lyons-ruth, et al., 2009; Goff, Gee, Telzer, Humphreys, Flannery, et al., 2013; Thomason & Marusak, 2017), the inferior parietal lobe and the superior temporal gyrus (Philip et al., 2014) in individuals that are exposed to ELS compared to non-abused participants. Strikingly, none of the studies were able to show the same hyper or hypo activity between the same areas
From the alterations reviewed so far, it seems that ELS impacts processes within the social, emotional and cognitive domains, by altering both brain structure and functioning. Transformations within these domains may be helpful whenever an individual is facing stress everyday by allowing them to enhance their coping strategy (McCrory et al., 2011). These adaptation may help to increase chances of survival or to save energy by not having to call upon brain areas but keep them ‘active’ all the time (Pechtel & Pizzagalli, 2011). However, when this stressor is no longer present, these brain changes might confer a risk to the ELS victims by increasing their vulnerability to mental health issues. In fact, there is a high prevalence of several mental health issues on people who suffered from ELS compared to their healthy controls. The most common known psychiatric disorders following ELS are: Mood Disorders (25%), Anxiety Disorders (24%), Substance Use Disorder (16%), Personality Disorder (16%), Eating Disorder (7%) and, Schizophrenia and Psychotic Disorders (7%) (Carr et al., 2013). Importantly, the mental health issues that ELS victims present are more persistent, recurrent and less likely to ameliorate following standard treatments in comparison to those suffered by non-abused individuals (Hovens et al., 2012; Nanni, Uher, & Danese, 2012), which underscores the great need for an optimized treatment (Monroe, Kupfer, & Frank, 1992). Thus, knowing that the development of mental health problems is tightly coupled to experiencing early life stress, and the
6 lack of proper treatment, stretches the importance of gaining knowledge and evidence on the underlying mechanisms of psychopathology and an effective treatment.
Extensive research has addressed the impact that ELS has on brain structure and functioning, but the findings on which areas and connectivity diverge, and this seems to be related to the age variability between the studied groups. It may occur that the brain adapts to the stress differently depending on the time that had passed after the ELS, and the moment the brain is investigated. Since ELS might still be present when a child is scanned, or might have stopped already at adolescence study cohorts, or many years before (if the ELS effects are studied in adulthood) this may affect how the brain is represented and has adapted prior to the moment research is carried. For example the review of Teicher, Samson, Anderson and Ohashi (2016) and Mccrory, Gerin and Viding (2017) report contradictory effects of ELS on brain function and structure. These reviews both include studies that use either children, adolescents or adults. Therefore, in this literature thesis I argue for a clear-cut approach to the study of the consequences of ELS on the brain that emphasize the age when the ELS occurred, the duration, the time when it ceased, and the time that passed by at the age of the victim at the time of the scan. This would help us elucidate how ELS impacts the brain structure and processes as a function of the brain developmental stage when the abuse occurred, and the potential mal- adaptation or resilient changes after the abuse ceased.
Early Life Stress and Functional Magnetic Resonance Imaging.
In the current review, I focus on studies that show alterations within brain structure and brain functioning, that make use of fMRI data. In addition, I focus on studies of children, adolescents and adults since I argue that the age of scanning brings forward a particular effect of ELS on brain structure and functioning. In order to do so, I will discuss four neurocognitive systems including threat processing, emotion regulation, reward processing and executive control. For every neurocognitive system I will provide a short description of the function of the system, the underlying brain structures, the influence of scanning age on the findings about that system’s functioning, likewise the influence on the brain structures and what role this might play in psychiatric disorders.
Threat Processing
One neurocognitive system which goes way back in evolution and therefore shared over multiple species is threat processing (Fox, Oler, Tromp, Fudge, & Kalin, 2015). To increase our survival threat processing is important for, in the first instance, to observe potentially dangerous stimuli and if necessary to respond to them (Mccrory, Gerin, & Viding, 2017). Since threat processing is an important defence mechanism research has been done in animals and humans which pointed towards the amygdala as the central area of a network involved in threat processing by detecting salient and dangerous stimuli (Robinson, Charney, Overstreet, Vytal, & Grillon, 2012). Within this network, the amygdala gets activated by signals originating from the thalamus, the superior colliculus (SC) and the pulvinar nucleus (PVN), and in turn, the amygdala sends its
7 projecting towards the striatum and the hypothalamus (Öhman, Carlsson, Lundqvist, & Ingvar, 2007). The amygdala also houses connections with other subcortical and cortical areas in order to adjust humans or rodents’ responses as reaction to their surroundings. For example, if a threatening stimuli is present most of the time without actually being harmful or on the other hand, harmful all the time, some responses to the stimuli can be redundant, so adjusting these responses can be optimised by costing an individual less energy (Shin & Liberzon, 2010). The areas involved in adjusting these responses and that have a mutual connection with the amygdala are known as the hippocampus, anterior insular (AI), the dorsal anterior cingulate cortex (dACC) and the ventromedial prefrontal regions (vmPFC) (Hung, Lou, & Taylor, 2012; Shin & Liberzon, 2010).
Why Threat Processing is Affected by ELS. While children are exposed to negative life events, stress levels mostly stay on a heightened level compared to individuals that never or barely experiences a form of trauma (Pollak & Sinha, 2002). During childhood, the brain is still developing and is very much influenced by events in the surrounding of a child (Curtis & Cicchetti, 2013). Due to the constant threat of negative events happening, the amygdala and other areas as the striatum and hippocampus are consistently in heightened activity in order to be able to react to threatening cues (Mccrory et al., 2017). As a result of this constant altered activity during the development of the brain and its heightened vulnerability during youth, this might lead towards long-lasting neurophysiological changes (Caldji, Diorio, & Meaney, 2003; Caldji et al., 1998). Depending on the reoccurrence, time span and onset of the ELS, additional brain areas can be affected on a more or less manner.
Age Dependent Effects of ELS on Brain Functioning and Structure During Threat Processing:
Age of Victimization and Scanning.
Within humans, the most common way to investigate the brain areas underneath threat processing is by the use of emotional faces tasks. The papers reviewed to investigate the functioning of brain area’s involved in threat processing can be found in table 1. From this studies, I specifically focus on fMRI data collected during the observation of emotional angry faces, which is most commonly used to investigate threat processing (Pichon, de Gelder, & Grèzes, 2009).
Brain Functioning and Brain Structure During Threat Processing in Children Exposed to Early Life Stress. Within table 1 three studies focused of fMRI data within children during threat processing (Luby, Botteron, Dietrich, Mcavoy, & Barch, 2014; Mccrory et al., 2011; Tottenham et al., 2011). As discussed earlier, the prominent area showing higher activity during threat processing within healthy humans is the amygdala (Robinson et al., 2012). Within children (mean age = 9.7) that are exposed to ELS, the amygdala shows hyperactivity when showed a threatful stimuli, compared to their healthy control group (Luby et al., 2014; Mccrory et al., 2011; Tottenham et al., 2011). Additionally, it seems that the AI is also affected in its functioning whenever a child (mean age = 9.7) has been exposed to ELS. Compared to healthy control groups, the AI, like the amygdala shows hyperactivity when threat is processed (Mccrory et al., 2011). Within the same children no
8 significant difference after exploration of brain volume were found about the influence of ELS on brain structure (Tottenham et al., 2011). So at this point the volume of the brain areas, even though of their altered activity, seems unchanged.
Brain Functioning and Brain Structure During Threat Processing in Adolescents Exposed to Early Life Stress. In comparison with children, it seems that apart from the amygdala and AI additional areas are influenced in their functioning by ELS. As for the children (mean age = 9.7), studies in adolescents (mean age = 14.35) show hyperactivation within the amygdala during threat processing compared to their healthy controls (Bellis & Hooper, 2012; Bogdan, Williamson, & Hariri, 2012; Ganzel, Kim, Gilmore, Tottenham, & Temple, 2013; Garrett et al., 2012; Mclaughlin, Peverill, Gold, Alves, & Sheridan, 2015; Mueller et al., 2010b). Three areas strongly connected to the amygdala during threat processing are the hippocampus, thalamus and the AI, and like the amygdala, they show hyperactivity compared to healthy controls (Crozier, Wang, Huettel, & Bellis, 2014; Garrett et al., 2012; Mclaughlin et al., 2015). These connections were also measured within children however, no alteration within these connections were found. Not only was the activity from the amygdala and hippocampus modified in adolescents that underwent ELS, but also the connection between them and the connections with more cortical areas. For example, compared to adolescents who did not experience ELS, in those who did the amygdala seem to present a weaker connection with the vmPFC (Goff, Gee, Telzer, Humphreys, Flannery, et al., 2013), while the hippocampus seems to have a stronger connection with the vmPFC (Lambert et al., 2017; Silvers et al., 2016).
Within children (mean age = 9.7) none of the reported studies showed an alteration after exploration in the volume of the amygdala and AI (Tottenham et al., 2011). However, in adolescents (mean age = 14.35) Ganzel et al. (2013) and Lambert et al. (2017) reported a differentiation from the norm size of the areas that showed a different functioning compared to healthy controls. As mentioned above the hippocampus, amygdala and AI showed enhanced activity in individuals that experienced ELS. Two studies that can be found in table 1 also looked into the volume of these areas (Ganzel et al., 2013; Lambert et al., 2017), they found that the volume of the hippocampus, amygdala and AI was lower compared to their healthy controls. Additionally, the vmPFC that is believed to have a reshaped connection with the hippocampus and amygdala showed a significant reduction in size. So it seems that compared to children (mean age = 9.7), adolescents (mean age = 14.35) start to show an effect on their brain structures while this was not the case in children yet. Within age groups the effect of ELS on brain structures seems to be in line with the found alterations in functioning.
Brain Functioning and Brain Structure During Threat Processing in Adults Exposed to Early Life Stress. During adulthood, the brain is fully grown and less vulnerable to external influences (e.g. maltreatment, abuse and a low social economic status), when adults (mean age = 32.19) were scanned during threat processing , other striking results were found compared to children (mean age = 9.73) and adolescents (mean age 14.35) with a history of ELS. These studies have observed that the hyperactivity of the amygdala and AI seems to be equal over the three stages of life, also during adulthood, the amygdala shows a significant increase in activity
9 compared to healthy controls (Fonzo et al., 2016; Herringa, Phillips, Fournier, Kronhaus, & Germain, 2013; Redlich et al., 2015; Tol et al., 2013). However, the activity of the hippocampus seems to be stabilised back to the same activity as healthy controls (Fonzo et al., 2019; Redlich et al., 2015; Tol et al., 2013; Zielinski et al., 2018). In contrast, the dACC is affected, compared to their healthy controls, adults exposed to ELS show a significant hypoactivity during threat processing (Fonzo et al., 2019; Fonzo et al., 2013; Zielinski et al., 2018). Strikingly, this hypoactivity of the dACC has not seen in children and adolescents yet. Additionally, hyperactivity was found in the vmPFC (Cisler et al., 2018; Jedd et al., 2015) and hypoactivity from the PVN (Nicol, Pope, Romaniuk, & Hall, 2015). Adolescents (mean age = 14.35) showed a weaker connection between the amygdala and vmPFC compared to their healthy controls. However, resting state functional neuroimaging in adults victims of ELS shows stronger connectivity between the amygdala and the vmPFC (Fonzo et al., 2013; Jedd et al., 2015). In contrast, as for adolescents who experienced ELS, a stronger connection between the hippocampus and vmPFC was also found during adulthood compared to matched healthy adults (Fonzo et al., 2013; Jedd et al., 2015). Furthermore, the connection between the amygdala and dACC is stronger in adults with a history with ELS compared to healthy controls, this was not found in adolescents or children (Won et al., 2015).
As aforementioned, studies in adolescents found a decrease in brain volume within the amygdala, hippocampus, AI and the vmPFC. Nonetheless, studies in adults showed that there was no difference is brain volume from the amygdala, hippocampus and AI. (Fonzo et al., 2016; Fonzo et al., 2013; Herringa et al., 2013). So the effects of ELS on the volume of these brain areas in adolescents seem to level out during adulthood. However, the volume of the vmPFC still shows a discrepancy compared to healthy controls, since it is significantly smaller in victims of ELS (Fonzo et al., 2016; Fonzo et al., 2013; Herringa et al., 2013; Jedd et al., 2015). Finally, Baker et al. (2013) shows with the use of a whole-brain analysis a decrease in volume of the ACC and the insula within individuals that experienced ELS.
The Effect of Early Life Stress on Behaviour and Psychopathology. Experiencing ELS goes hand in hand with alterations in the threat processing system. Modifications within the functioning or areas involved in threat processing are argued to be a possible cause in the development of Posttraumatic Stress Disorder (PTSD), Anxiety Disorders (AD), depression and Drug Addiction (AD) (Etkin & Wager, 2007; Kerestes, Davey, Stephanou, Whittle, & Harrison, 2014; Lanius et al., 2017; Shechner et al., 2012; Sripada, Angstadt, McNamara, King, & Phan, 2011; Wald et al., 2013). Within children, McCrory et al. (2017) argued that the pattern of neural activation found in children with ELS reflects an adaptation to environmental threat instead of actual damage as found within people returning from combat. However, in adults with PTSD, the amygdala hyperreactivity is still present, so it might be that this short term adaptive changes can in the long term contribute to an increased risk of psychopathology including PTSD (Mccrory et al., 2017).
The most common way to treat patients with PTSD is Cognitive Behavioural Therapy (CBT). Unfortunately, we have learned that CBT is almost never effective in people that experienced ELS (17.7%, Targum & Nemeroff, 2019). This could be a result from the fact that most people suffering from PTSD
10 after returning from combat solely show alterations within the amygdala. However, in during childhood, adolescents and adulthood, patients that experienced ELS seem to have more affected areas as for example the AI. This could mean that other forms of therapy or even combinations are necessary to treat ELS suffered individuals. Individuals who underwent ELS seem to have more affected brain areas compared to same condition patients that never suffered from ELS, other therapeutic interventions might be necessary to reduce the risk of psychopathology development or curing a disorder.
Table 1: Functional magnetic resonance brain imaging studies investigating the effect of early life stress on brain functioning and brain structure during threat processing
Paper Age N Form of ELS Performed Task
Bogdan et al. (2012)
11-15 years 279 Emotional Neglect Hariri (EFAT)
Crozier, Wang, Huettel, & De Bellis (2014)
11-13 years 74 Abuse & Neglect Oddball
Dannlowski et al. (2013)
Adults 150 Child Maltreatment Subliminal Affective Priming
De Bellis & Hooper (2012)
10-18 years 16 Abuse & Neglect Oddball
Fonzo et al. (2013)
Adults 33 Child Maltreatment Hariri (EFAT)
Fonzo et al. (2016)
Adults 182 Child Maltreatment Hariri (EFAT)
Ganzel, Kim,
Gilmore, Tottenham, & Temple (2013)
10-15 years 14 Severe Life Events Passive viewing
Garrett et al. (2012)
10-16 years 46 Interpersonal Trauma Gender Discrimination
Gee et al. (2013)
6.5-17.6 years 89 Previous Institutionalization Indicate Neutral Faces Grant et al. (2015)
Adults 34 Childhood Trauma Threat Learning
Herringa et al. (2013)
Adults 28 Child Maltreatment Dynamic Faces
Jedd et al. (2015)
Adults 71 Child Maltreatment Hariri (EFAT)
Lambert et al. (2017)
8-19 years 60 Exposure to violence Context Memory
Lee et al. (2015)
Adults 31 Verbal Abuse Gender Discrimination
Maheu et al. (2010)
9-18 years 30 Previous Institutionalization Altering Attention McCrory et al. (2011)
11 McLaughlin, Peverill,
Gold, Alves, & Sheridan (2015)
13-19 years 42 Child Maltreatment Emotion Regulation
Nicol et al. (2015)
Adults 36 Child Trauma Gender Discrimination
Redlich et al. (2015)
Adults 377 Child Maltreatment Hariri (EFAT)
Silvers et al. (2016)
7-16 years 46 Previous Institutionalization Threat Learning Skokauskas,
Carballedo, Fagan, & Frodl (2015)
Adults 80 Sexual Abuse Attention Shifting
Suzuki et al. (2014)
Children 115 Early-Life Trauma Gender Discrimination
Tottenham et al. (2011)
Children 44 Previous Institutionalization Go/No-Go
van Harmelen et al.
(2013) Adults 135 Child Emotional Maltreatment Gender Discrimination
Emotion Regulation
In the study of emotion regulation it is commonly said that emotions come to us whenever something important is a stake (Gross, 2002). These emotions can arise automatically and in other times they come to us after deep considerations, which can also be seen as conscious and unconscious emotions (LeDoux, 1995). These emotions need to be regulated in order for us to respond to our environment in an appropriate way. By regulating our emotions we can change the activated emotions, their valence, duration and intensity (Cole, Martin, & Dennis, 2004; Nancy Eisenberg & Spinrad, 2004). Sometimes automatic generated emotions do not contribute in a positive way to the behaviour or action we have to undertake in order to solve problems in our environment. In this case we need a conscious regulation to steer our emotions and thereby our following actions into a more sensible way (Ochsner et al., 2004).
In order to investigate the brain areas involved in emotion regulation studies involving neuroimaging and the observation of patients with brain lesions have been especially helpful. These studies identified a strongly interconnected network of subcortical/ limbic structures and the frontal cortical regions (Mccrory et al., 2017). The limbic structures involved mostly in automatic generated emotions identified as the striatum, amygdala and insula (Ochsner, Silvers, & Buhle, 2012). Automatic generated emotions need guidance to generate appropriate reactions and behaviour, the areas which are responsible for this conscious top down control are the ACC, mPFC and the lateral prefrontal cortex (lPFC) (Hariri, Mattay, Tessitore, Fera, & Weinberger, 2003; Kim, Somerville, Johnstone, Alexander, & Whalen, 2003). Why Emotion Regulation is Affected by ELS. Children who grow up in a negative surrounding and bad parent-child interaction are mostly exposed to negative emotions. For example for maltreated parent-children, on the
12 moment they would show any emotion, they would often be corrected in a negative abusive way (Howes, Cicchetti, Toth, & Rogosch, 2000). Research has shown that when a child is corrected with the use of negative consequences instead of parental support, this would lead to disruptions in biological and neuroregulatory mechanisms (Calkins, 1994), which in later life causes poor emotional regulation and reactivity towards frustration (Kim-Spoon, Cicchetti, & Rogosch, 2013). These changes in biological and neuroregulatory mechanisms during childhood might lead to remaining alterations within the brain (Blair & Diamond, 2008). Depending on the intensity of ELS and frequency of occurrence, the affected brain areas might differ over individuals, especially compared to children that enjoyed parental support when being emotional (Eisenberg et al., 2001). Thereby, ELS provokes the release and modifies the expression of a considerable amount of stress mediators and neurotransmitters within clear-cut brain regions. The interaction of these mediators with evolving neurons and neuronal networks may lead to abiding structural and functional alterations correlated with cognitive and emotional consequences (Chen & Baram, 2016).
Age Dependent Effects of ELS on Brain Functioning and Structure During Emotion Regulation:
Age of Victimization and Scanning.
Within humans, the most common way to investigate the brain areas underlying emotion regulation is by the use of emotional go/no-go task (Pechtel & Pizzagalli, 2011). The affective Go/NoGo task can evaluate emotional response inhibition and emotional response speed and therefore may be useful for assessing whether emotional regulation differs from the norm characterized by abnormalities in deliberate or automatic emotion regulation (Chiu, Holmes, & Pizzagalli, 2008). The papers reviewed to investigate the functioning of brain area’s involved in threat emotion regulation can be found in table 2. These papers use a form of emotional go/no-go task, which for example could be matching emotional faces.
Brain Functioning and Brain Structure During Emotion Regulation in Children Exposed to Early Life Stress. As showed in table 2, four studies focused on the effect of early life stress on emotion regulation with the use of fMRI (Gee et al., 2013; Marusak, Martin, Etkin, & Thomason, 2015; Puetz et al., 2014, 2016). After reviewing these papers, the activation during emotion regulation seems to be altered in two prominent areas in children that experienced ELS (mean age = 11.47). First of all, the amygdala shows, in regard to threat processing, an enhanced activity during the task compared to healthy controls, perhaps in order to more rapidly adapt their emotional response (Gee et al., 2013; Marusak et al., 2015). Additionally, in contrast to the amygdala, the prefrontal cortex shows a reduced response during the task in children that experienced ELS (Marusak et al., 2015; Puetz et al., 2014, 2016). Task-related functional connectivity between the dlPFC-dACC and between the amygdala-vmPFC was observed in children that experienced ELS compared to their healthy controls, which is interesting since these patterns of activation are generally solely found in healthy adults during emotion regulation (Gee et al., 2013; Puetz et al., 2014). In my knowledge and literature, up to date, no studies have successfully reported differences in brain structures involved in emotion regulation . Brain Functioning and Brain Structure During Emotion Regulation in Adolescents Exposed to Early Life Stress. As for children (mean age = 11.47), the amygdala in adolescents (mean age = 16.40) shows an enhanced activity
13 during emotion regulation when an individual has experienced ELS (Mclaughlin et al., 2015; Won et al., 2015). However, in contrast to the children, adolescent show an hyperactivity instead of reduced activity in the prefrontal cortex (Elsey et al., 2015; Hart et al., 2016; Won et al., 2015). Furthermore, additional areas that seem to be affected in their activity by ELS are the insular cortex and the ACC, which both show an increased activity in adolescent that experienced ELS compared to their healthy controls (Elsey et al., 2015; Hart et al., 2016; Mclaughlin et al., 2015). Likewise, in terms of connectivity, adolescents also show a decreased connectivity between the amygdala-vmPFC during the task. Additionally, the connectivity between amygdala-ACC and vmPFC-insula seem to be reduced. However, compared to children, the reduced connectivity between the dlPFC-dACC seem to be back to the strength of connectivity as for healthy controls. In terms of structural changes, to my knowledge, no research has been done in adolescents which looked at brain structural changes in regions associated with emotion regulation.
Brain Functioning and Brain Structure During Emotion Regulation in Adults Exposed to Early Life Stress. Within adults (mean age = 34.85), there is research done investigating the structural changes in the areas involved in emotion regulation. These studies showed with the use of ROI analysis that in particular the ACC has a reduced gray matter volume in individuals who experience ELS during their childhood (Cohen et al., 2006; Dannlowski et al., 2011). In adults who experienced ELS, the ACC shows a reduced activity during emotion regulation, whereas in adolescents (mean age = 16.40) the ACC showed a hyperactivity (Cohen et al., 2006; Dannlowski et al., 2011).
Of the studies reviewed in this section, it is clear that the amygdala shows a steady hyperactivation during emotion regulation throughout life, since this hyperactivation was present in children, adolescents and adults that experienced ELS. For the activity and connectivity between other areas mentioned within children (mean age = 11.47) and adolescent, in adulthood it seems that the activity and connectivity with other areas found their way back towards the activity seen in healthy controls, while the connectivity patterns between children and adolescents differ not only with control peers participants, but also between them. The Effect of Early Life Stress on Behaviour and Psychopathology. Emotion regulation an essential skill that allow us to socialize and function in a society. Alteration within this system can go hand in hand with psychiatric disorders as anxiety, depression and DA (Abravanel & Sinha, 2015; Aldao, Nolen-Hoeksema, & Schweizer, 2010; Mennin, Holaway, Fresco, Moore, & Heimberg, 2007; Nolen-Hoeksema & Aldao, 2011). As a result of ELS, the functioning of amygdala and other brain areas -depending of the stage of life are affected within the emotion regulation system and therefore might be a risk factor for developing psychiatric conditions in the future (Kim & Cicchetti, 2010; McLaughlin, Hatzenbuehler, Mennin, & Nolen-Hoeksema, 2011; Shields & Cicchetti, 2001).
Psychiatric disorders like anxiety and depression are mostly treated with pharmacotherapy and CBT, unfortunately, it seems that only a small portion of people who have experienced ELS are responsive to these treatments. However, again similar to threat processing, patients that suffered from ELS show modified functionality depending on their stage of life and more areas are affected compared to controls
14 that solely have a disorder (McCrory et al., 2017). Because of the patters of brain activity in different cohorts of ELS victims, age-specific interventions might be necessary in order to reduce the risk on potential future psychopathology or curing ongoing psychopathologies (Gratz, Weiss, & Tull, 2015). In current days, researchers have focused on parent-child interaction therapy and child-parent psychotherapy instead of CBT and it seems to be more successful (Chaffin et al., 2004). However, this treatment only seems to be affective when the ELS is still ongoing, so for the other life phases other forms of suitable therapies should be found. Table 2: Functional magnetic resonance brain imaging studies investigating the effect of early life stress on brain functioning and brain structure during emotion regulation.
Paper Age N Form of ELS Performed Task
Cohen et al. (2006)
Adults 250 Sexual Abuse Current Emotional Distress
Dannlowski et al. (2011)
Adults 148 Child Maltreatment Face Matching
Paradigm Demers et al. (2017)
Adults 80 Child Maltreatment Matching Task
Elsey et al. (2015)
14-18 years 67 Child Maltreatment The guided-imagery
Gee et al. (2013)
6-11 years 48 Institutionalization Emotional Face Task
Hart et al. (2018)
12-20 years 70 Physical Abuse Emotion Discrimination Task
Lee et al. (2015) 14-18 years 43 Verbal Abuse Emotional Face Task Maruskak et al. (2015)
8-12 years 51 Childhood Trauma Emotional Face Task
McLaughlin et al. (2015)
13-19 years 42 Child Maltreatment International Affective Picture System
Puetz et al. (2014)
8-11 years 25 Separation Cyberball
Puetz et al. (2016) 10-12 years 40 Child Maltreatment Rejection Words
Reward Processing
The third cognitive domain I want to discuss is the domain of reward processing, a system that is also considered crucial for coping with and learning from our environment (Scott-Van Zeeland, Dapretto, Ghahremani, Poldrack, & Bookheimer, 2010). Like emotion regulation, a human being can learn in a conscious and unconscious way from a reward, this was already embellished a long time ago by Pavlov (Bruno, 2019). In the conscious way, we know what kind of behaviour we have to show or not show our peers in order to get a rewarded for our behaviour. However, it could also be the case that we get rewarded by our peer without being aware of the fact that we show a particular kind of behaviour (Bruno, 2019).
15 The brain areas which are pointed out by rodent studies and neuroimaging studies involved in reward processing are known as the ventral striatum, ACC and orbitofrontal cortex (OFC) (Bartels & Zeki, 2004; Knutson & Cooper, 2005; O’Doherty, Deichmann, Critchley, & Dolan, 2002; Spreckelmeyer et al., 2009; Thut et al., 1997). All three of these areas are responsible for unconscious and conscious reward processing (Pelphrey, Adolphs, & Morris, 2004). Even though reward processing has a positive tone, receiving a punishment also falls underneath this cognitive domain (O’Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001). So, especially for individuals that are used to being exposed to an environment where punishment plays a head role (like ELS), learning from how to respond to this and which behaviour they should not show is very important.
Why Reward Processing is Affected by ELS. During childhood, children that are exposed to early life stress in general underwent and experienced an increased amount of stress due to the abuse, maltreatment or low social economic status (McCrory et al., 2017). The effect of stress on the development of the brain mostly targets areas within the reward processing system. Due to the enhanced stress, lower levels of neural signalling within the striatum of rats are found (Andersen & Teicher, 2009). In case of lower signalling within the striatum during childhood and thereby vulnerable periods from brain development could lead to permanent consequence on the brain (Meaney, Brake, & Gratton, 2002; Pizzagalli, 2014). Depending on the stage of the vulnerable periods each brain area is in, brain areas can be affected differently across individuals.
Age Dependent Effects of ELS on Brain Functioning and Structure During Reward Processing:
Age of Victimization and Scanning
The most common way to investigate which brain areas are functionally involved in reward processing are tasks that use either a social or monetary award (Knutson & Cooper, 2005; O’Doherty et al., 2001; Scott-Van Zeeland et al., 2010). The papers reviewed to investigate the differences of functional contribution of areas during reward processing in people with ELS and healthy controls can be found in table 3. The task that are done by the participants mostly involve getting a primary award or punishment involving happy faces or a secondary reward or punishment with the use of money or points (Mccrory et al., 2017).
Brain Functioning and Brain Structure During Reward Processing in Children Exposed to Early Life Stress. In table 3, we can find eight studies which focus on reward processing in children (mean age = 11.97) exposed to ELS (Fareri et al., 2017; Gerin et al., 2013; Goff, Gee, Telzer, Humphreys, Gabard-Durnam, et al., 2013; Hanson, Hariri, & Williamson, 2015; Marshall et al., 2018; Marusak, Hatfield, Thomason, & Rabinak, 2017; Marusak et al., 2015; Takiguchi et al., 2015). As aforementioned, brain areas involved in reward processing include the ACC, OFC and the ventral striatum. Research has shown that the ventral striatum shows decreased activity during reward processing in children exposed to ELS (Hanson, Hariri, et al., 2015). Additionally, a discrepancy can be found in terms of connectivity of the ventral striatum and the mPFC. On the one hand, Marshall et al. (2018) show a decreased connectivity between the ventral striatum and the mPFC during reward processing. On the other hand, Fareri et al. (2017) shows enhanced connectivity between the ventral
16 striatum and the mPFC. This discrepancy can be due to the fact that they use a population with about two years in between. Furthermore, the ventral striatum seems to have an increased connectivity with the lPFC and the cerebellum (Marshall et al., 2018). No difference in activity was found in the ACC and the OFC. Two additional brain areas were found with altered activation. Namely, the nucleus accumbens (Nacc) and the caudate nucleus, which both show a decreased activation during reward processing in children who experienced ELS (Gerin et al., 2013; Goff, Gee, Telzer, Humphreys, Gabard-Durnam, et al., 2013; Takiguchi et al., 2015). As far as my knowledge goes, up to date, no research succeeded in showing a alteration of brain structures related to reward processing in children exposed to ELS.
Brain Functioning and Brain Structure During Reward Processing in Adolescents Exposed to Early Life Stress. Five studies in table 3 focused on reward processing in adolescents (mean age = 15.7) that experienced ELS (Casement et al., 2014; Dennison et al., 2016; Fareri et al., 2017; Hanson, Hariri, et al., 2015; Mehta et al., 2010). Like children (mean age = 11.97), adolescents present an increased. activity within the striatum during reward processing (Hanson, Hariri, et al., 2015) Contrastingly, a study by Casement et al. (2014) found hyperactivity of the ventral striatum , which again can be due to the fact that they use population with a age difference of three years. Furthermore, as observed in children, adolescents also show an increased connectivity during reward processing between the ventral striatum and the mPFC (Fareri et al., 2017). Again, to my knowledge no studies were able to report structural difference during adolescents after ELS exposure.
Brain Functioning and Brain Structure During Reward Processing in Adults Exposed to Early Life Stress. Compared to children (mean age = 11.97) and adolescents (mean age = 15.7), more research has been done investigating the effect of ELS in brain function in reward processing during adulthood (mean age = 23.7: Baker, Williams, Korgaonkar, et al., 2013; Baranger et al., 2016; Birn, Roeber, Pollak, & Reyna, 2017; Boecker-Schlier et al., 2016; Boecker et al., 2014; Casement, Shaw, Sitnick, Musselman, & Forbes, 2013; Dillon, Holmes, Birk, Brooks, Lyons-Ruth, et al., 2009; Holz et al., 2017; Morgan, Shaw, & Forbes, 2014). In contrast other processes, research shows that more brain areas are affected by ELS in their functioning during reward processing as compared to earlier life stages. Like in children and adolescents, adults present a decreased activity of the ventral striatum during reward processing (Baranger et al., 2016; Boecker-Schlier et al., 2016; Boecker et al., 2014; Holz et al., 2017; Morgan et al., 2014), along with decreases in the ACC, putamen and the mPFC (Birn et al., 2017; Boecker-Schlier et al., 2016; Boecker et al., 2014; Casement et al., 2013; Morgan et al., 2014). Additionally, there is some contradictory findings within the insula, since Birn et al. (2017) observed hypoactivity and Boecker et al. (2014) found hyperactivity. All studies mentioned above do not elaborate on any adapted form of connectivity in the brain during reward processing. Finally, as mentioned before, Baker et al. (2013) shows with the use of a whole-brain analysis a decrease in volume of the ACC and the insula which as for threat processing are important areas in reward processing. The Effect of Early Life Stress on Behaviour and Psychopathology. The ventral striatum and ACC are two important areas during reward processing. Reduced activity within the ventral striatum is linked with various forms of pathological behaviour, including depression, anxiety and drug addiction (Balodis & Potenza, 2015;
17 Diekhof, Kaps, Falkai, & Gruber, 2012; Forbes & Dahl, 2012; Ubl et al., 2014; Weiland et al., 2014; White et al., 2017, 2016). The activity during reward processing tasks seems to be reduced during childhood, adolescence and adulthood. Studies have shown that this decrease of activity can be a predictor for the pathologies like depression and anxiety (Bress, Foti, Kotov, Klein, & Hajcak, 2013), even though, a particular individual might not show any signs (Telzer, Fuligni, Lieberman, & Galván, 2014). Rodents studies have shown that a decrease in signalling of the ventral striatum results in depression-like behaviour and hyperactive neural response towards addictive substances (Kosten, Xiang, & Kehoe, 2005; Matthews & Robbins, 2003; Romano-López, Méndez-Díaz, Ruiz-Contreras, Carrisoza, & Prospéro-García, 2012; Vetulani, 2013).
The hypoactivity of the ventral striatum, thus seems to be an important area to intervene with in order to decrease the risk of developing a form of psychopathology. However, in people that have experienced ELS it seems that not only the ventral striatum is important in developing a disorder, but also the ACC, which might partially explain why suitable treatment for people that suffer from drug addiction do work for patients that never experienced ELS, but less often work for individuals that did experience ELS. Research has shown that solely treating for the substance abuse in individuals that experienced ELS is not enough, but that adding CBT including trauma exposure to the substance abuse treatment is necessary in order for the therapy to be a success (Brady & Back, 2012). Additionally, adolescents therapy that include child-parents psychotherapy seems to be successful in avoiding substance abuse in the future (Dishion, Nelson, & Kavanagh, 2003).
Table 3: Functional magnetic resonance brain imaging studies investigating the effect of early life stress on brain functioning and brain structure during reward processing.
Paper Age N Form of ELS Performed Task
Baker et al. (2013) Adults 173 Child Maltreatment Emotional Images Baranger et al. (2016)
Adults 665 Abuse and Neglect Reward-guessing task
Birn et al. (2017)
Adults 23 Child Maltreatment MID
Boecker et al. (2014)
Adults 162 Early Family Adversity MID
Boecker-Schlier et al. (2016)
Adult 168 Childhood Family Adversity MID
Casement et al. (2014)
16 years 120 Abuse and Neglect Reward-guessing task
Casement et al. (2015)
Adults 157 Childhood Trauma Reward-guessing task
Dennison et al. (2016) 13-20 years 59 Abuse and Neglect Viewing Social-Images Dillon et al. (2009)
Adults 44 Child Maltreatment MID
18 Fareri et al. (2017) 11-18 years 28 Institutionalisation Social Funcioning Gerin et al. (in press) 10-15 years 41 Neglect and Abuse Passive-avoidance task Goff et al. (2013)
5-10 years 69 Institutionalisation Emotional Faces Task
Hanson et al. (2015)
11-15 years 106 Emotional Neglect Reward-guessing task
Hanson et al. (2016) Adults 72 Parental loss Card-guessing task Holz et al. (2017) Adults 171 Childhood Family Adversity MID
Marshall et al. (2018) 6-17 years 100 Low Income Family Reward task Marusak et al. (2015) 12 years 51 Childhood Trauma Conflict task
Marusak et al. (2016) 7-17 years 43 Childhood Trauma Emotional Image Task Mehta et al. (2010) 16 years 23 Institutionalisation MID
Morgan et al. (2014) Adults 20 Emotional Neglect Reward-guessing task Takiguchi et al. (2015) 10-15 years 36 Abuse and Neglect Gambling task
Executive Control
Last but not least, I will discuss executive control, which is the capability to plan, anticipate and think about daily activities. Not just thinking about the outcome in daily activities falls underneath executive control but also thinking about the goals you want to achieve in the long term (McAuley & White, 2011). In general, executive control contains three different key aspects. First of all, there is working memory, which is crucial to keep given information online, until it does not contribute anymore for a given task, behaviour or conversation (Miyake et al., 2000). Additionally, there is inhibition which allows suppression of dominant automatic behavioural responses which might, when showed, have a negative effect on the goals you want to achieve (Hofmann, Schmeichel, & Baddeley, 2012). Last, task shifting allows you to shift amongst simultaneous events in your surroundings (Funahashi, 2001).
Research brings forward that executive control is maintained by an interplay between cortical and subcortical areas. The cortical areas which are involved are known as the lateral and dorsomedial frontal cortex and the more posterior parietal areas. These areas are in turn connected to subcortical areas known as the basal ganglia and the thalamus (Rubia, 2011). Together they make our day-to-day activities and long-term goals easier to achieve (Snyder, 2013).
Why Executive Control is Affected by ELS. Children exposed to early life adversity and institutional neglect show an increased activity within areas that regulate executive control (Mueller et al., 2010a). This heightened
19 activity is mostly linked to decrease neural efficiency and require overall greater effort in particular tasks (McCrory et al., 2017). This decreased neural efficiency during the brain development and its sensitive periods might cause a lifelong alteration within brain areas that are involved during executive control (Andersen et al., 2008). Not much research has been done investigating the effect of ELS on executive control, but it might be the case that different brain areas are permanently affected or modified in its functioning variably between individuals.
Age Dependent Effects of ELS on Brain Functioning and Structure During Executive Control:
Age of Victimization and Scanning.
Commonly, executive functions and the involved brain areas are researched with the use of a sort stop-signal task, or a task that includes task or rule switching (Baddeley, Della Sal, Robbins, & Baddeley, 1996; Schall & Godlove, 2012). The papers reviewed in order to see a difference between ELS experienced people and health controls and their summoned brain areas during executive control can be found in table 4. Compared to the other three domains, executive functions in relation to ELS is understudied. To my knowledge in all the life periods no studies were able to show significant structural changes in relation to ELS and executive control.
Brain Functioning and Brain Structure During Executive Control in Children Exposed to Early Life Stress. Two of the studies reviewed for the effect of ELS on brain functioning during executive control were focused on children (mean age = 9.3, see table 4, (Demir-Lira et al., 2016; Mueller et al., 2010a). These studies showed that compared to healthy controls, children that are exposed to ELS show altered increased connectivity between the lateral frontal cortex and the temporal/parahippocampal areas during tasks involving executive functions (Demir-Lira et al., 2016). Additionally, the ACC, vlPFC, basal ganglia and insular show hyperactivity during the same tasks (Demir-Lira et al., 2016; Mueller et al., 2010a).
Brain Functioning and Brain Structure During Executive Control in Adolescents Exposed to Early Life Stress. Within adolescents (mean age = 15.89), two studies investigated the effect of ELS on brain functioning during tasks involving executive function (Harms, Shannon Bowen, Hanson, & Pollak, 2018; Lim et al., 2015). These studies showed the same hyperactivity of the vlPFC and the ACC as in children (mean age = 9.3), in addition to hyperconnectivity between the cerebellum and the putamen. However, unlike in children, the group of adolescents in the study of Harms et al. (2018) failed to observe increased connectivity between the basal ganglia and the insula.
Brain Functioning and Brain Structure During Executive Control in Adults Exposed to Early Life Stress. Solely one study was found that investigated the effect of ELS in executive functions during adulthood (mean age = 37.4, Philip et al., 2013). This study showed that compared to their healthy controls, adults that had experienced ELS show a reduced activity of the ACC, vlPFC, middle/superior frontal gyrus and middle temporal regions, which is in direct contrast found for activation of these areas in children (mean age = 9.3) and adolescents (mean age = 15.89) who showed an increased activity.
20 The Effect of Early Life Stress on Behaviour and Psychopathology. Problems with executive control are mostly linked to psychopathologies like depression, OCD, PTSD and psychosis (Cortese et al., 2012; Eysenck, Derakshan, Santos, & Calvo, 2007; Holmes et al., 2005; Rubia, 2011; Snyder, 2013; Snyder, Miyake, & Hankin, 2015). These problems and psychopathologies mostly go hand in hand (Aron, 2011; Tu, Lee, Chen, Li, & Su, 2013). However, there are also people that do not show any form of a psychopathology, but they do show difficulties with executive control during mirroring of behaviour or social interactions (Snyder, Kaiser, Warren, & Heller, 2015; Snyder, Miyake, et al., 2015). Multiple studies have shown that mutations in brain activity during executive control are strong predictors for the development of these psychopathologies in later stages of life (Campbell & Von Stauffenberg, 2009; Cannon et al., 2006; Evans, Kouros, Samanez-Larkin, & Garber, 2016; Han et al., 2016; Parslow & Jorm, 2007). As shown above not much research addressed the effects of ELS on brain functioning during executive control, a skill that may be an important predictor for multiple disorders.
From the little amount of research done, there can be seen that ELS does have an effect on brain function depending on the age of an individual. So, depending on the age of the individual it could be the case that different forms of therapy are necessary. A great example is the fact that treating OCD in children and adolescents that have experienced ELS do not respond well on CBT only but needs an intervention that include interaction with family members as well in order to be successful (Renshaw, Steketee, & Chambless, 2005).
Table 4: Functional magnetic resonance brain imaging studies investigating the effect of early life stress on brain functioning and brain structure during executive functions.
Paper Age N Form of ELS Performed Task
Demir-Lira et al. (2016)
4-6 years 16 Physical Abuse Reversal Learning
Harms et al. (2015)
14-17 years 53 Physical Abuse Instrumental Learning
Lim et al. (2015)
13-20 years 22 Childhood Abuse Stop-Signal Task
Mueller et al. (2010)
11-15 years 12 Institutionalization Change-Task Task
Philip et al. (2013)
Adults 10 Physical and Sexual Abuse Working Memory Task
Conclusion
Within the current literature there is an apparent discrepancy on which brain areas and their activity are affected by ELS as can been seen from the contrary effects reported by the review of Teicher et al. (2016) and McCrory et al. (2016). This thesis explored one factor which could have had an influence on these
21 divergent findings, namely the age of researched participants when they are assessed. The effects of ELS on the brain could be subject to confounds due to ages of the studied cohorts and the different patterns of brain activity observed. Therefore, I argue that the reported effects of ELS vary so dramatically due to the fact that the age of the victims varies at the moment of scanning.
Future, studies should be cautiously considered depending on the age group used while conducting the research. In order to visibilize the age-dependent effects of ELS and age of assessment, four cognitive domains which are known to be affected by early live stress were discussed. Within these cognitive domains (threat processing, reward processing, emotion regulation and executive functions) the participants used in the bulk of research papers discussion, one of these domains were separated over three age groups (children, adolescents and adults). After separating the participants, included in the various studies, in these three groups, more consistent results per group were found. It seems that between age groups, different brain areas show altered brain activity or structures. The fact that the brain areas are affected differently depending on the age group makes sense, due to the fact that children might still undergo ELS, while adolescent might still undergo ELS or just escaped from it or experience less, while adults have been bygone from the trauma experienced during childhood. Additionally, since the brain still develops throughout life, ongoing stress or prolonged stress responses within the brain causes a brain to develop in a different way than non-maltreated individuals, which explain that other brain areas seem to be altered per study cohort (Knudsen, 2004). Mclaughlin, Sheridan and Lambert (2014) argued that the deprivation and threat related structural brain changes during childhood are associated with age-specific reductions in cortical thickness as a result of decreases in dendritic arborization, spines, and density. This alterations within the neuronal basis of the brain, affects different kind mechanisms while the brain is developing, causing functional differences when a brain in scanned during particular stages in life, which highlights the importance of across research separations of ages while talking about general results of ELS on brain structure and functioning. Thereby, there is argued that ELS causes cumulative physiological dysregulation from childhood onwards, this cumulative reaction, causes ongoing changes within the brain during lifetime (Dich et al., 2015). This means that the brain keeps changing during the whole period of life due to the events in childhood, causing for different effects on brain function and structure pending of the stage in life.
Nowadays, all patients that suffered from ELS are treated therapeutically more or less in the same way, namely with Cognitive Behavioural Therapy. However, if we look at the results of this thesis, more focus should lie on which particular brain areas in what particular age group show reshaped activity or brain structures. If these alterations in brain activity and brain structure are pointed out, a more specific treatment plan can be made, for example by combining different forms of therapy, in order to give the patients the help they need. Due to additional brain alterations instead of solely typical brain transformations in people with a particular form of psychopathology, mostly standardised therapeutic treatment for a particular psychopathology is still unsuccessful in individuals exposed to adverse early-life events (Targum & Nemeroff, 2019). It seems that ELS has more harmful consequences on the brain and can be moderated by various contributors and these all have their own authentic way to affect the brain during development.
22 Unfortunately, this thesis only explores one aspect that possibly moderates the effect of ELS on the brain. However, ELS is such a complex stressor that the influence it might have on the brain should be explored from various angles, since there are multiple factors that could also moderate the severity of the effect of ELS on the brain. Exploring and separating all the possible contributors is necessary in order to get a complete view of how and when the brain is affected however, it is usually the case that the ELS is mixed. Therefore, the researched population, as also argued by Mclaughlin, Sheridan, & Lambert (2014), should be separated on type of trauma, however mostly different forms of trauma like physical and emotional abuse go hand in hand, so it might be difficult to isolate. Another option would be to count the number of adversities and disparate forms of stress. Since Benjet, Borges and Medina-Mora (2010) argued that the number and types of adversities is nonlinear, such that the odds of altered brain functioning increased with increasing numbers of adversities. However, the odds increased at a decreasing rate. Furthermore, the age of onset of the ELS could make a difference on how the brain is affected. During the development of the brain in childhood, there are sensitive periods (Knudsen, 2004). Sensitive periods are periods were particular brain areas develop depending on gene expression, as a results, whenever an area is within the sensitive period of their development, the gene expression can be reshaped by environmental interactions (Crews, He, & Hodge, 2007; Lupien et al., 2009). So depending on the onset of ELS and which area is in its sensitive period at that time, that areas can be affected worse than others (Andersen et al., 2008; Heim & Binder, 2012). Thereby, animal and human research showed, that depending on the timing and duration of chronic stress, other hormones like glucocorticoid can vary in levels causing for divergent effects on the brain, behaviour and cognition during lifespan (Lupien et al., 2009). Also, the gender of the child might be of big importance in order to pin point which areas are affected the most, since hormone levels differ and might be affected authentically by ELS depending on the gender. Additionally, there will always be individual differences in, for example, the genes of an isolated individual which might make it difficult to draw general conclusions. Depending on which genes are affected by which environmental mediators, other neural mechanisms will be affected causing for long-lasting changes within differing brain area’s (Chen & Baram, 2016). This already elucidates that there are so many contributors that might all have their own influence on the development of the brain, causing for explicit affects and differences between individuals that were touched by ELS.
From the paragraph above, one can learn that making clear-cut separations on how ELS modifies the brain is challenging. One difficulty encountered within this thesis is the separation of age groups. Within the bulk of research done in the past it is difficult to find age boundaries for child, adolescent and adults, since some papers will consider an 18-year-old participant as an adolescent while the other paper calls the participant an adult. Within this paper the boundary for children was up to the age of 13, adolescents until the age of 20 and adults from 21 and onwards. However, I think that future research should focus on separating the population not solely on age, but rather a focus on which hormonal levels suits what age category the best. When distinguished on hormonal levels a more precise boundary can be made to decide which person should belong to what group. When this is done more matching results in affected brain
23 activity and structure can be found per group, since hormones also have their own effect on brain functioning.
In addition, human researchers might consider to think about working together with other researchers that are involved in rodent research. Since, a downside in human fMRI research is that it is only correlational research, conclusions in fMRI research are mostly drawn from seeing two or more processes happening at the same time. However, what the actual mechanism behind the altered brain activity is, is not known. One way to investigate these deep-down mechanisms is with the use of rodents. Unlike with humans, it is allowed to do invasive research with rodents. The results might not be directly translational but it is a start in giving insight in the neuronal mechanisms that are influenced by ELS.
Taken together, in order to investigate the consequence of ELS on brain activity and brain structure within the cognitive domains of threat, reward, emotion and executive control, the age of the trauma and of the assessment as along with other moderators should be further considered to get clear and demarcated results. These outcomes are necessary so we can find the most convenient therapeutic treatment models in order to stabilize coping mechanisms, which are of great importance during a situation of ELS but pathological when still used if the stressor is diminished. This thesis already made a head start in pointing at the age-dependent effects of ELS in the brain. However, much work needs to be done in setting clear boundaries in age, gender, type of ELS, individual differences and hormone levels in order to understand and aid at the effects of ELS on the brain.
24
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